The work outlined in this program project grant focuses on novel strategies to achieve long term disease free survival and potential cure of myeloma. We believe this is possible only with 1. achievement of minimal residual disease (MRD) status using high dose therapy; and 2. use of novel immunological approaches to treat MRD. This program is comprised of 4 Projects and 3 Cores which interact on both a scientific and clinical level to achieve this goal. In Project 1 we will concentrate on the reasons for failure of allogeneic transplant in this disease, specifically by investigating the biology of the graft-versus myeloma effect. As a result of this work, it is expected that antigen-specific T cells will be generated for subsequent use in the clinical trial setting to eradicate MRD that remains after allogeneic transplant. Project 2 will be dedicated to improving the results of autologous transplantation in myeloma by 1) developing technologies to provide tumor-free autografts and 2) identifying methods to generate and expand anti-myeloma specific autologous T cells ex vivo for adoptive transfer and treatment of MRD post autografting. In Project 3 we will determine the feasibility the inducing an active immune response against myeloma antigens such as DF3 in preclinical models and use this information to undertake clinical trials of vaccination in myeloma. This will be coupled with adoptive therapies to treat MRD post allografting and autografting as outlined in Projects 1 and 2. Project 4 will similarly attempt to induce an immune response to a recently discovered, potentially important tumor-specific virus, namely Human Herpes Virus 8 (HHV8) in myeloma. Administrative and Clinical Support (A) and Biostatistical (B) Cores will assist design, conduct, analysis and reporting of laboratory and clinical studies. Molecular Biology and Immune Assessment Core (C) will assess MRD in myeloma and provide immunological monitoring after these novel therapies. To ensure its success, we have assembled a highly diverse yet interactive collaborative team of molecular biologists, immunologists, transplant biologists, and clinicians with a long track record of successful collaboration and with extensive translational experience to drive our basic science discoveries to clinical experimentation.